Brief Communication
Vitamin C Pharmacokinetics: Implications for Oral and
Intravenous Use
Sebastian J. Padayatty, MRCP, PhD; He Sun, PhD, CBS; Yaohui Wang, MD; Hugh D. Riordan, MD; Stephen M. Hewitt, MD, PhD;
Arie Katz, MD; Robert A. Wesley, PhD; and Mark Levine, MD
Background: Vitamin C at high concentrations is toxic to cancer
cells in vitro. Early clinical studies of vitamin C in patients with
terminal cancer suggested clinical benefit, but 2 double-blind,
placebo-controlled trials showed none. However, these studies
used different routes of administration.
Objective: To determine whether plasma vitamin C concentra-
tions vary substantially with the route of administration.
Design: Dose concentration studies and pharmacokinetic model-
ing.
Setting: Academic medical center.
Participants: 17 healthy hospitalized volunteers.
Measurements: Vitamin C plasma and urine concentrations
were measured after administration of oral and intravenous doses
at a dose range of 0.015 to 1.25 g, and plasma concentrations
were calculated for a dose range of 1 to 100 g.
Results: Peak plasma vitamin C concentrations were higher after
administration of intravenous doses than after administration of
oral doses (P < 0.001), and the difference increased according to
V itamin C in gram doses is taken orally by many people
and administered intravenously by complementary
and alternative medicine practitioners to treat patients with
advanced cancer (1, 2). After oral intake, vitamin C plasma
concentrations are tightly controlled at 70 to 85 mol/L
for amounts (as much as 300 mg daily) that can be ob-
tained from food (3, 4). However, concentrations achieved
by higher pharmacologic doses are uncertain. Despite poor
rationale, vitamin C in gram doses was proposed as an
anticancer agent decades ago (5). Unblinded studies with
retrospective or nonrandom controls reported clinical ben-
efit from oral and intravenous vitamin C administered to
patients with terminal cancer at a dosage of 10 g daily (1,
6, 7). Placebo-controlled trials in patients with cancer re-
ported no benefit from oral vitamin C at a dosage of 10 g
daily (8, 9), and vitamin C treatment was judged ineffec-
tive (10). However, in vitro evidence showed that vitamin
C killed cancer cells at extracellular concentrations higher
than 1000 mol/L (11, 12), and its clinical use by some
practitioners continues.
We recognized that oral or intravenous routes could
produce substantially different vitamin C concentrations
(13). We report here that intravenous doses can produce
plasma concentrations 30- to 70-fold higher than the max-
imum tolerated oral doses. These data suggest that the role
of vitamin C in cancer treatment should be reexamined,
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dose. Vitamin C at a dose of 1.25 g administered orally produced
mean (SD) peak plasma concentrations of 134.8 20.6 mol/L
compared with 885 201.2 mol/L for intravenous administra-
tion. For the maximum tolerated oral dose of 3 g every 4 hours,
pharmacokinetic modeling predicted peak plasma vitamin C con-
centrations of 220 mol/L and 13 400 mol/L for a 50-g intra-
venous dose. Peak predicted urine concentrations of vitamin C
from intravenous administration were 140-fold higher than those
from maximum oral doses.
Limitations: Patient data are not available to confirm pharma-
cokinetic modeling at high doses and in patients with cancer.
Conclusions: Oral vitamin C produces plasma concentrations
that are tightly controlled. Only intravenous administration of
vitamin C produces high plasma and urine concentrations that
might have antitumor activity. Because efficacy of vitamin C treat-
ment cannot be judged from clinical trials that use only oral
dosing, the role of vitamin C in cancer treatment should be re-
evaluated.
Ann Intern Med. 2004;140:533-537. www.annals.org
For author affiliations, see end of text.
and insights from vitamin C pharmacokinetics can guide
its clinical use.
METHODS
Pharmacokinetic Studies in Healthy Persons
The study was approved by the Institutional Review
Board of the National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health. After
we obtained written informed consent, 17 healthy volun-
teers (7 men, 10 women; age, 19 to 27 years) were studied
as inpatients by using a depletion-repletion study design
(3, 4). Participants were hospitalized for 3 to 6 months and
consumed a vitamin C deficient diet containing less than
0.005 g of vitamin C per day. At plasma vitamin C con-
centrations less than 8 mol/L, persons were depleted
without signs of scurvy. Vitamin C, 0.015 g twice daily,
was then administered orally until participants achieved a
steady state for this dose (0.03 g daily). Participants re-
ceived successive oral daily vitamin C doses of 0.03 g,
0.06 g, 0.1 g, 0.2 g, 0.4 g, 1.0 g, and 2.5 g until a steady
state was achieved for each dose. Bioavailability sampling
was conducted at a steady state for vitamin C doses of
0.015 g, 0.03 g, 0.05 g, 0.1 g, 0.2 g, 0.5 g, and 1.25 g. For
each bioavailability sampling, vitamin C was administered
in the fasting state. After oral administration, blood sam-
ples were collected at 0, 15, and 30 minutes and at 1, 1.5,
6 April 2004 Annals of Internal Medicine Volume 140 Number 7 533
 Brief Communication Oral and Intravenous Vitamin C
Context
Clinical studies of vitamin C as a potential anticancer
agent have produced inconsistent results despite in vitro
evidence that high concentrations kill cancer cells.
Contribution
Pharmacokinetic studies in healthy persons, using a deple-
tion-repletion design, show that intravenous administration
can achieve 70-fold higher blood levels of vitamin C than
the highest tolerated oral dose.
Cautions
Although this study provides better understanding of the
pharmacokinetic issues involved in research on vitamin C,
it provides no evidence that vitamin C has any effect on
cancer cells and cannot be used to support its clinical use
for therapeutic purposes.
The Editors
2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
19, 22, and 24 hours (3, 4). After intravenous administra-
tion at 250 mg/min, blood samples were collected at 0,
2.5, 5, 10, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, 3.5,
4, 5, 6, 7, 8, 9, and 10 hours. Data obtained from bio-
availability samplings were used to determine peak plasma
and urine vitamin C concentrations.
Pharmacokinetic Modeling
We used data from 7 men to construct a unique
3-compartment vitamin C pharmacokinetic model with
parameters describing saturable absorption, tissue distribu-
tion, and renal excretion and reabsorption (14). This
model was used to predict peak plasma and urine vitamin
C concentrations attained when pharmacologic doses of
the vitamin are administered. For intravenous administra-
tion, it was assumed that vitamin C was infused at a rate of
1 g/min, and urine output was 100 mL/h.
Vitamin C Assay
Vitamin C was measured by using high-performance
liquid chromatography with coulometric electrochemical
detection (3, 4, 15).
Statistical Analysis
We compared plasma vitamin C concentration curves
(against either dose or time) by repeated-measures analyses
of variance (ANOVA). In addition to the repeating factor
(dose or time), other factors considered were sex and route
of administration. In the comparison of routes of admin-
istration at multiple doses, in which sex not only was an
important factor itself but also had an important interac-
tion with route, separate ANOVA were determined for
men and women to assess the importance of route of ad-
ministration. Analyses were performed by using DataDesk,
version 5 (1995) (Data Description, Inc., Ithaca, New
York).
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Role of the Funding Source
The funding source had no role in the design, con-
duct, and reporting of the study or in the decision to sub-
mit the manuscript for publication.
RESULTS
When 1.25 g of vitamin C was given intravenously,
plasma concentrations were significantly higher than when
the vitamin was given orally (P 0.001 by repeated-mea-
sures ANOVA) (Figure 1). In addition, plasma concentra-
tions were significantly higher over all doses (P 0.001 by
repeated-measures ANOVA) with intravenous compared
with oral administration (Figure 1, inset). At the highest
dose of 1.25 g, mean peak values from intravenous admin-
istration were 6.6-fold higher than mean peak values from
oral administration. When all doses were considered, peak
plasma vitamin C concentrations increased with increasing
intravenous doses, whereas peak plasma vitamin C concen-
trations seemed to plateau with increasing oral doses. Urine
vitamin C concentrations were higher for the same dose
given intravenously compared with that administered by
the oral route. At the highest dose of 1.25 g, peak urine
concentrations from intravenous administration were ap-
proximately 3.5 times higher than from oral administration
(data not shown).
The 3-compartment vitamin C pharmacokinetic
model that we developed predicted that a single oral dose
of 3 g, the maximum tolerated single dose, produced a
peak plasma concentration of 206 mol/L (Figure 2, top).
Peak predicted concentration after a single 1.25-g oral dose
was slightly lower at 187 mol/L. For 200 mg, an amount
obtained from vitamin Crich foods, peak predicted con-
centration was approximately 90 mol/L. Plasma concen-
trations for all of these amounts returned to steady-state
values, approximately 70 to 85 mol/L, after 24 hours.
With 3 g given orally every 4 hours, the maximum tolera-
ble (6), peak predicted plasma concentration was approxi-
mately 220 mol/L (Figure 2, top). By contrast, after in-
travenous administration, predicted peak plasma vitamin C
concentrations were approximately 1760 mol/L for 3 g,
2870 mol/L for 5 g, 5580 mol/L for 10 g, 13 350
mol/L for 50 g, and 15 380 mol/L for 100 g (Figure 2,
bottom). Doses of 60 g given intravenously are used for
cancer treatment by complementary and alternative medi-
cine practitioners (2). Predicted peak urine vitamin C con-
centrations were as much as 140-fold higher after intrave-
nous administration compared with oral administration
(data not shown).
DISCUSSION
Our data show that vitamin C plasma concentrations
are tightly controlled when the vitamin is taken orally,
even at the highest tolerated amounts. By contrast, intra-
venous administration bypasses tight control and results in
concentrations as much as 70-fold higher than those
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 Oral and Intravenous Vitamin C Brief Communication
Figure 1. Plasma vitamin C concentrations in healthy volunteers after intravenous or oral administration of vitamin C.

Plasma vitamin C concentrations are shown as a function of time after the 1.25-g oral or intravenous dose administered at steady state for that dose in
12 persons (3 men, 9 women). Inset: Peak plasma vitamin C concentrations as a function of dose after oral or intravenous administration of vitamin C.
Seventeen persons (7 men, 10 women) received doses from 0.015 to 0.1 g, 16 persons (6 men, 10 women) received the 0.2-g dose, 14 persons (6 men,
8 women) received the 0.5-g dose, and 12 persons (3 men, 9 women) received the 1.25-g dose. Persons received each dose while at steady state for that
dose.

achieved by maximum oral consumption. Both findings
have clinical relevance.
Vitamin C oral supplements are among the most pop-
ular sold, and gram doses are promoted for preventing and
treating the common cold, managing stress, and enhancing
well-being (1). Our data show that single supplement gram
doses produce transient peak plasma concentrations that at
most are 2- to 3-fold higher than those from vitamin
Crich foods (200 to 300 mg daily). In either case, plasma
values return to similar steady-state concentrations in 24
hours. Because differences in plasma concentrations from
supplements and from food intake are not large, supple-
ments would be expected to confer little additional benefit,
a finding supported by available evidence (16, 17).
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However, consumption of fruits and vegetables, which
contain vitamin C, is beneficial for unknown reasons (16,
17). On the basis of current knowledge and the pharma-
cokinetics presented here, physicians should advise their
patients to consume fruits and vegetables, not vitamin C
supplements, to obtain potential benefits.
Just as important, our data show that intravenous ad-
ministration of vitamin C produces substantially higher
plasma concentrations than can be achieved with oral ad-
ministration of vitamin C. This difference was previously
unrecognized and may have treatment implications. Case
series published by Cameron, Campbell, and Pauling (l, 6,
7) have been controversial. In these series, several hundred
patients with terminal cancer treated with 10 g of vitamin
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 Brief Communication Oral and Intravenous Vitamin C

Figure 2. Predicted plasma vitamin C concentrations in healthy persons after oral (top) or intravenous (IV ) (bottom)
administration of vitamin C.

The 3-compartment pharmacokinetic model used to calculate these values was derived from data in 7 healthy men (3, 14). Baseline values are 70 to 85
mol/L, the expected steady-state plasma vitamin C concentration for healthy persons with a vitamin C intake of more than 0.2 g/d.

C intravenously for 10 days and then 10 g orally indefi-
nitely were compared with more than 1000 retrospective
and prospective controls. Patients treated with vitamin C
survived 150 to 300 days longer than controls (1, 6, 7).
Other researchers reported benefit consisting of increased
survival, improved well-being, and reduced pain (1). All of
these studies were uncontrolled, and factors unrelated to
intervention may have affected outcome. Two randomized,
double-blind, placebo-controlled studies from the Mayo
Clinic found no benefit (8, 9). These studies included 200
patients who were treated with 10 g of vitamin C daily.
The Mayo Clinic studies were considered to be definitive
(10). However, in these studies, vitamin C was given
orally, which is in contrast to the intravenous and oral use
in other studies. On the basis of our pharmacokinetic data,
we conclude that the Mayo Clinic studies, which used oral
administration of vitamin C, are not comparable to studies
536 6 April 2004 Annals of Internal Medicine Volume 140 Number 7
with intravenous administration. The Mayo Clinic studies
neither support nor refute possible effects of intravenously
administered vitamin C on cancer.
Intravenous vitamin C may have a role in the treat-
ment of cancer as a result of the plasma concentrations that
can be achieved only by this route. With consumption of 5
to 9 servings of fruits and vegetables daily, steady-state
plasma concentrations are 80 mol/L or less, and peak
values do not exceed 220 mol/L, even after maximum
oral administration of 3 g 6 times daily. By contrast, intra-
venous vitamin C may produce plasma concentrations as
high as 15 000 mol/L. At extracellular concentrations
greater than 1000 mol/L, vitamin C is toxic to cancer
cells, although mechanisms and interpretation are contro-
versial (11, 12, 18). The vitamin C free radical species,
ascorbyl radical, is detectable in animals only when they
receive intravenous vitamin C equivalent to a 10-g dose in
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 Oral and Intravenous Vitamin C
humans (19). We propose that detectable ascorbyl radical
forms only when human plasma concentrations are greater
than 1000 mol/L and that either the radical itself or its
unpaired electron induces oxidative damage that can be
repaired by normal but not cancer cells. Understanding
mechanisms of cytotoxicity may further the investigational
use of vitamin C in patients with cancer, used alone or
with other agents that potentiate such actions (20). Al-
though minimal data are available, intravenous vitamin C
is expected to have little toxicity compared with conven-
tional chemotherapeutic agents (3). In this context and in
light of our new pharmacokinetic data, a role for intrave-
nous vitamin C in cancer treatment should be reevaluated.
From the National Institute of Diabetes and Digestive and Kidney Dis-
eases, the National Cancer Institute, and the Clinical Center, National
Institutes of Health, Bethesda, Maryland; the Food and Drug Adminis-
tration, Rockville, Maryland; and Bio-Communications Research Insti-
tute, Wichita, Kansas.
Grant Support: By a grant from the National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health (Z01 DK
54506). Dr. Katz received partial support from the Office of Dietary
Supplements, Office of the Director, National Institutes of Health.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Mark Levine, MD, Molecular and Clin-
ical Nutrition Section, Building 10, Room 4D52MSC 1372, National
Institutes of Health, Bethesda, MD 20892-1372.
Current author addresses and author contributions are available at www
.annals.org.
References
1. Cameron E, Pauling L. Cancer and Vitamin C. Philadelphia: Camino Books;
1993.
2. Riordan NH, Riordan HD, Meng X, Li Y, Jackson JA. Intravenous ascorbate
as a tumor cytotoxic chemotherapeutic agent. Med Hypotheses. 1995;44:207-13.
[PMID: 7609676]
3. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal
KR, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a
recommended dietary allowance. Proc Natl Acad Sci U S A. 1996;93:3704-9.
[PMID: 8623000]
4. Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary
www.annals.org
Downloaded From: http://annals.org/ on 01/03/2017
Brief Communication
allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A.
2001;98:9842-6. [PMID: 11504949]
5. McCormick WJ. Cancer: a collagen disease, secondary to a nutritional defi-
ciency. Arch Pediatr. 1959;76:166-71. [PMID: 13638066]
6. Cameron E, Campbell A. The orthomolecular treatment of cancer. II. Clinical
trial of high-dose ascorbic acid supplements in advanced human cancer. Chem
Biol Interact. 1974;9:285-315. [PMID: 4430016]
7. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of
cancer: reevaluation of prolongation of survival times in terminal human cancer.
Proc Natl Acad Sci U S A. 1978;75:4538-42. [PMID: 279931]
8. Creagan ET, Moertel CG, OFallon JR, Schutt AJ, OConnell MJ, Rubin J,
et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients
with advanced cancer. A controlled trial. N Engl J Med. 1979;301:687-90.
[PMID: 384241]
9. Moertel CG, Fleming TR, Creagan ET, Rubin J, OConnell MJ, Ames
MM. High-dose vitamin C versus placebo in the treatment of patients with
advanced cancer who have had no prior chemotherapy. A randomized double-
blind comparison. N Engl J Med. 1985;312:137-41. [PMID: 3880867]
10. Wittes RE. Vitamin C and cancer [Editorial]. N Engl J Med. 1985;312:
178-9. [PMID: 3965937]
11. Leung PY, Miyashita K, Young M, Tsao CS. Cytotoxic effect of ascorbate
and its derivatives on cultured malignant and nonmalignant cell lines. Anticancer
Res. 1993;13:475-80. [PMID: 8517665]
12. Sakagami H, Satoh K, Hakeda Y, Kumegawa M. Apoptosis-inducing activ-
ity of vitamin C and vitamin K. Cell Mol Biol (Noisy-le-grand). 2000;46:129-43.
[PMID: 10726979]
13. Padayatty SJ, Levine M. New insights into the physiology and pharmacology
of vitamin C. CMAJ. 2001;164:353-5. [PMID: 11232136]
14. Graumlich JF, Ludden TM, Conry-Cantilena C, Cantilena LR Jr, Wang Y,
Levine M. Pharmacokinetic model of ascorbic acid in healthy male volunteers
during depletion and repletion. Pharm Res. 1997;14:1133-9. [PMID: 9327438]
15. Washko PW, Welch RW, Dhariwal KR, Wang Y, Levine M. Ascorbic acid
and dehydroascorbic acid analyses in biological samples. Anal Biochem. 1992;
204:1-14. [PMID: 1514674]
16. Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, et al. Vitamin C
as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr.
2003;22:18-35. [PMID: 12569111]
17. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in
adults: scientific review. JAMA. 2002;287:3116-26. [PMID: 12069675]
18. Clement MV, Ramalingam J, Long LH, Halliwell B. The in vitro cytotox-
icity of ascorbate depends on the culture medium used to perform the assay and
involves hydrogen peroxide. Antioxid Redox Signal. 2001;3:157-63. [PMID:
11291594]
19. Wang X, Liu J, Yokoi I, Kohno M, Mori A. Direct detection of circulating
free radicals in the rat using electron spin resonance spectrometry. Free Radic Biol
Med. 1992;12:121-6. [PMID: 1313773]
20. Grad JM, Bahlis NJ, Reis I, Oshiro MM, Dalton WS, Boise LH. Ascorbic
acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells.
Blood. 2001;98:805-13. [PMID: 11468182]
6 April 2004 Annals of Internal Medicine Volume 140 Number 7 537
 Current Author Addresses: Dr. Padayatty, Wang, and Levine: Molec-
ular and Clinical Nutrition Section, Building 10, Room 4D52MSC
1372, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD
20892-1372.
Dr. Sun: Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857.
Dr. Riordan: Bio-Communications Institute, 3100 North Hillside Ave-
nue, Wichita, KS 67219.
Dr. Hewitt: National Cancer Institute, ATC 225D, MSC 4605, Na-
tional Institutes of Health, Bethesda, MD 20802-4605.
Dr. Katz: Molecular and Clinical Nutrition Section, Building 10, Room
6C432B, National Institutes of Health, 9000 Rockville Pike, Bethesda,
MD 20892.
Dr. Wesley: Clinical Center, Building 10, Room 10S246 MSC 1871,
National Institutes of Health, 9000 Rockville Pike, Bethesda, MD
10892.
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Author Contributions: Conception and design: S.J. Padayatty, H. Sun,
Y. Wang, H.D. Riordan, S.M. Hewitt, M. Levine.
Analysis and interpretation of the data: S.J. Padayatty, H. Sun, Y. Wang,
A. Katz, R.A. Wesley, M. Levine.
Drafting of the article: S.J. Padayatty, A. Katz, M. Levine.
Critical revision of the article for important intellectual content: S.J.
Padayatty, H. Sun, Y. Wang, H.D. Riordan, S.M. Hewitt, A. Katz, M.
Levine.
Final approval of the article: S.J. Padayatty, H. Sun, Y. Wang, H.D.
Riordan, S.M. Hewitt, A. Katz, M. Levine.
Provision of study materials or patients: H.D. Riordan, M. Levine.
Statistical expertise: R.A. Wesley.
Obtaining of funding: M. Levine.
Administrative, technical, or logistic support: Y. Wang, M. Levine.
Collection and assembly of data: S.J. Padayatty, H. Sun, Y. Wang, H.D.
Riordan, A. Katz, M. Levine.
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